Journal Article

CCR2 chemokine receptor signaling mediates pain in experimental osteoarthritis

Tran, Phuong B, Ghoreishi-Haack, Nayereh, Das, Rosalina, Ren, Dongjun, Miller, Rachel E, Malfait, Anne-Marie, Miller, Richard J

2012

Overview

Osteoarthritis is one of the leading causes of chronic pain, but almost nothing is known about the mechanisms and molecules that mediate osteoarthritis-associated joint pain. Consequently, treatment options remain inadequate and joint replacement is often inevitable. Here, we use a surgical mouse model that captures the long-term progression of knee osteoarthritis to longitudinally assess pain-related behaviors and concomitant changes in the innervating dorsal root ganglia (DRG). We demonstrate that monocyte chemoattractant protein (MCP)-1 (CCL2) and its high-affinity receptor, chemokine (C-C motif) receptor 2 (CCR2), are central to the development of pain associated with knee osteoarthritis. After destabilization of the medial meniscus, mice developed early-onset secondary mechanical allodynia that was maintained for 16 wk. MCP-1 and CCR2 mRNA, protein, and signaling activity were temporarily up-regulated in the innervating DRG at 8 wk after surgery. This result correlated with the presentation of movement-provoked pain behaviors, which were maintained up to 16 wk. Mice that lack Ccr2 also developed mechanical allodynia, but this started to resolve from 8 wk onwards. Despite severe allodynia and structural knee joint damage equal to wild-type mice, Ccr2 -null mice did not develop movement-provoked pain behaviors at 8 wk. In wild-type mice, macrophages infiltrated the DRG by 8 wk and this was maintained through 16 wk after surgery. In contrast, macrophage infiltration was not observed in Ccr2 -null mice. These observations suggest a key role for the MCP-1/CCR2 pathway in establishing osteoarthritis pain.

• Publisher: National Academy of Sciences,National Acad Sciences
• Subject: animal models / Animals / Arthritis / Arthritis, Experimental - genetics / Arthritis, Experimental - immunology / Arthritis, Experimental - pathology / Arthritis, Experimental - physiopathology / Behavioral neuroscience / Biological Sciences / CCR2 receptor / chemoattractants / chemokine CCL2 / Chemokine CCL2 - genetics / Chemokine CCL2 - immunology / Chemokine CCL2 - physiology / Chemokines / Chronic pain / Disease Models, Animal / ganglia / Ganglia, Spinal - immunology / Ganglia, Spinal - pathology / Ganglia, Spinal - physiopathology / gene expression regulation / Humans / Hyperalgesia - genetics / Hyperalgesia - immunology / Hyperalgesia - physiopathology / Macrophages / Macrophages - pathology / Male / messenger RNA / Mice / Mice, Inbred C57BL / Mice, Knockout / monocytes / Neurons / Osteoarthritis / Osteoarthritis - genetics / Osteoarthritis - immunology / Osteoarthritis - pathology / Osteoarthritis - physiopathology / Pain / Pain - genetics / Pain - immunology / Pain - physiopathology / Receptors / Receptors, CCR2 - deficiency / Receptors, CCR2 - genetics / Receptors, CCR2 - physiology / RNA, Messenger - genetics / RNA, Messenger - metabolism / Rodents / Signal Transduction / surgery / T cell receptors